Anti-arrhythmic agents

Quinidine, Procainamide, Disopyramide*,

Lidocaine, Tocainide, Mexilitine, Phenytoin
Lorcainide,
Sotalol
Amiodarone,
Verapamil, Diltiazem
 Arrhythmia

Arrhythmia is deviation of heart

from normal RHYTHM.

Arrhythmia of the heart occurs when

either initiation or propagation of a heart-beat stimulus happens
abnormally.

Antiarrhythmic agent is a drug that is capable

of reverting irregular cardiac rhythm or rate to normal
Heart

Normal rhythym
Atria contract (ventricles fill up)
Atria relax
Ventricles contract (blood is pumped out)
Ventricles relax
Next beat………………
 Rhythm of the Heart

• Intrinsic stimulation
• Nervous (Control) Stimulation
 Rhythm of the Heart
Intrinsic stimulation

• SA node – Intrinsic pacemaker for the heart initiates impulses more rapidly than other
groups of neuromuscular cells. SA node -------- AV node -------- AV bundle of His
– Characterized by automaticity
• depolarize spontaneously
– normal firing rate –
• between 60-100 impulses per minute.
– Atria contract first
• Established rhythm is conducted to the AV node
– Ventricles fill
• The impulse is transmitted to the Bundle of His
– Ventricles contract and
• pump out oxygenated blood into aorta and
• deoxygenated blood to the lungs
• Regular, rhythmic electrical signals keep the heart pumping blood to the lungs and the body.
 Rhythm of the Heart
Nervous stimulation

In addition to the intrinsic impulses, the heart can be

stimulated by
• Sympathetic nerves
– supply the SA, AV nodes and the atrial and ventriclar
muscle.
– Sympathetic stimulation
• increases the rate and force of the heart beat.
• Parasympathetic nerves
– supply the SA, AV nodes and atrial muscle.
– Parasympathetic stimulation
• reduces the rate at which impulses are
produced,
• decreasing the rate and force of the heart
beat
 Normal Heart beat

ECG-represents a ‘cardiac cycle’

• P-wave specifically designates the
electrical activity which passes
over the atrial surface
0.06-0.1s
Ventricular
contraction • Q, R, S-waves, (i.e., the QRS-
0.08-0.1s
complex) are produced by the
Atrial
Ventricular ventricles
relaxation
contraction

• T-wave is produced by the

repolarization of the ventricular
muscle fibres
0.34-0.42s
 Arrhythmia - Irregular Heart beat
The atrial contraction and ventricular contraction are not synchronised
Atrial fibrillation
• Multiple erratic, weak electric impulses
generated from various places in the atria
• Reduced cardiac output
• Heart unable to provide adequate blood
flow and therefore oxygen to the rest of
the body.

Ventricular fibrillation
• Disorganised and very rapid contraction
of ventricles.
• Disruption of ventricular function.
• Reduced/No cardiac output
• Heart unable to provide adequate blood
flow and therefore oxygen to the rest of
the body. 
 Atrial fibrillation

Absence of P waves,
Atrial Fibrillation Disorganized electrical activity instead of P wave,
Irregular R-R intervals due to irregular
conduction of impulses to the ventricles
Normal

Treatment
Reduction in heart rate would give it time to coordinate between
atria and ventricles (complete filling before contraction)
 Ventricular fibrillation

ECG shows an irregular chaotic trace

Normal
with no recognizable wave pattern

Treatment
Reduction in heart rate would give it time to coordinate between
atria and ventricles (complete filling before contraction)
ARRHYTHMIAS
Sinus arrythmia

Supra Ventricular
Atrial arrhythmia Tachyarrythmia
(SVT)
Nodal arrhythmia
(junctional)

Ventricular arrhythmia
 Myocardial action potential

In automatic tissues In non-automatic tissues

(SA node, AV node) (Atria, Ventricles)
 Cardiac Action Potential

https://www.youtube.com/watch?v=v7Q9BrNfIpQ
Action potential of the heart

In the SA node and In the atria and

AV node, AP curve ventricles the AP
consists of 3 phases curve consists of 5
phases
 Cardiac Action Potential- SA/AV nodes

Intrinsic stimulation Adrenergic stimulation

0 3

• Phase 4 : slow depolarization

(less than -40mV) voltage gated Na channels open Adrenergic stimulation – Increases heart rate
– enhance slow depolarisation phase
– Na ions move in
– Enhance fast depolarisation phase
• Phase 0: Fast depolarization
Cholinergic stimulation – Decreases heart rate
(at -40mV) Opening of voltage gated Ca channels – decreasing slow depolarisation phase
– Ca ions move in – decreasing fast depolarisation phase
• Phase 3: Repolarisation
(at +10mV) voltage gated Ca channels close, voltage gated K channels open
– K ions move out
• Ion distribution across membranes is restored by several other ion pumps and the cycle starts again……
 Cardiac Action Potential
Voltage-gated ion channels in the cardiomyocyte

schematic diagram of the cardiac electrical activity

Phase 0 – Na channels open – Na ions move in - rapid depolarisation

Phase I – Closing of Na channels, Opening of K channels - K ions move out – Beginning of repolarisation
Phase II – Opening of Ca channels, K channels open – Ca ions move in, K ions move out – muscle contracts – Plateau
Phase III – Ca channels close, K channels open – Repolarisation
Phase IV – Resting membrane potential
The slope of phase 0 = conduction velocity

effective refractory period (ERP)

Time between phase 0 and 3
• In this period the cell can’t be excited
 Arrhythmia
Treatment
Reduction in heart rate would give it time to coordinate between
atria and ventricles (complete filling before contraction)

The heart rate can be modulated by

• controlling the movement of Na, K and Ca transport into and
out of the cardiac cell during an action potential.
• sympathetic / parasympathetic modulation
Heart rate can be decreased by….
Blocking Na channels
SA/AV node Cardiac Myocyte

Normal rhythm Blocked Na channel

Blocking inactivated Na channels Blocking activated Na channels

• Decreased automaticity • Prolong Depolarisation,
• Decreased conductivity • Decreased conductivity
Heart rate can be decreased by….
Blocking K channels

Blocking K channels
• Prolong Repolarisation
• Prolong effective refractory period
Heart rate can be decreased by….
Blocking Ca channels
SA / AV- node Cardiac myocyte

•Decreased rate of depolarisation • Short plateau

(decreased conductivity) • Decreased muscle contraction
(force of contraction)
 Heart rate can be decreased by….
Blocking sympathetic activity with -blockers
• Blocks sympathetic stimulation heart via βI adrenergic receptors
• They raise the threshold of excitation
• Decrease the frequency of SA node firing
• Heart rate decreases
• Used for atrial and ventricular arrhythmias
Anti-arrhythmic agents
Quinidine, Procainamide, Disopyramide*,
Lidocaine, Tocainide, Mexilitine, Phenytoin
Lorcainide,
Sotalol
Amiodarone,
Verapamil, Diltiazem
 Classification
Antiarrhythmic drugs can therefore be subdivided into four main groups.

• Na channel blockers – Class I • β-adrenergic blockers – Class II

– Class IA – Action potential duration – Sotalol
prolonged (moderate Na+ channel
blockade)
• Quinidine, Procainamide, • K channel blockers – Class III
Disopyramide
– Amiodarone
– Class IB – Action potential duration
shortened (weak Na+ channel
blockade) • Ca channels blockers – Class IV
• Lidocaine, Tocainide – Verapamil, diltiazem,
Mexiletine, Phenytoin
– Class IC – Action potential duration
unaffected (strong Na+ channel
blockade)
• Lorcainide
 Class I: Na+ Channel Blockers

• Na+ Channel Blockers affect Phase 0 of Action potential.

• This class is further subclassified into class IA, IB, and IC based on the
primary pharmacologic effect.
• IA:
• Moderate Na+ channel blockade
• Prolong APD
• IB:
• Weak Na+ channel blockade
• Shorten APD in some heart tissues
• IC:
• Strong Na+ channel blockade
• Minimal effect on APD
 Class I: Na+ Channel Blockers

• Sodium-channel blockers comprise the

Class I antiarrhythmic compounds
according to the Vaughan-Williams
classification scheme.
• These drugs bind to and block the fast
sodium channels that are responsible
for the rapid depolarization (phase 0) of
fast-response cardiac action potentials.
• This type of action potential is found in
non-nodal, cardiomyocytes (e.g., atrial
and ventricular myocytes; purkinje
tissue).
 Class I: Na+ Channel Blockers

• Because the slope of phase 0 depends on the

activation of fast sodium-channels and the
rapid entry of sodium ions into the cell (Figure:
Na+ in), blocking these channels decreases the
slope of phase 0, which also leads to a
decrease in the amplitude of the action
potential.
• In contrast, nodal tissue action potentials
(sinoatrial and atrioventricular nodes) do not
depend on fast sodium channels for
depolarization; instead, phase 0 depolarization
is carried by calcium currents.
• Therefore, sodium-channel blockers have no
direct effect on nodal tissue, at least through
the blockade of fast sodium-channels.
 Effects on depolarisation
• The principal effect of reducing the rate and
magnitude of depolarization by blocking sodium
channels is a decrease in conduction velocity in
non-nodal tissue (atrial and ventricular muscle,
purkinje conducting system).
• The faster a cell depolarizes, the more rapidly
adjacent cells will become depolarized, leading to a
more rapid regeneration and transmission of
action potentials between cells.
• Therefore, blocking sodium channels reduces the
velocity of action potential transmission within the
heart (reduced conduction velocity; negative
dromotropy).
• This can serve as an important mechanism for
suppressing tachycardias that are caused by
abnormal conduction
 Effects on repolarisation
• Besides affecting phase 0 of
action potentials, sodium-channel
blockers may also alter the action
potential duration (APD) and
effective refractory period (ERP).
• Because some sodium-channel
blockers increase the ERP (Class
IA), while others decrease the
ERP (Class IB) or have no effect on
ERP (Class IC), the Vaughan-
Williams classification recognizes
these differences as subclasses of
Class I antiarrhythmic drugs.
 Effects on repolarisation
• These effects on ERP are not directly
related to sodium channel blockade, but
instead are related to drug actions on
potassium channels involved in phase 3
repolarization of action potentials.
• These channels regulate potassium
efflux from the cell (K+ out), and
therefore repolarization. The drugs in
these subclasses also differ in their
efficacy for reducing the slope of phase
0, with IC drugs having the greatest and
IB drugs having the smallest effect on
phase 0 (IA drugs are intermediate in
their effect on phase 0).
Classification Mechanism Primary site of Examples
action
Class IA Atrial and Quinidine
(Na+ channel • Prolong Depolarisation - Ventricular tissue Procainamide
blockers) Decreased conductivity Diisopyramide
• Moderate • Prolong duration of action
Na+ • Prolong effective refractory
channel period - Decreased
blockade excitability
• Prolong
APD

Quinidine Procainamide Diisopyramide

Drugs of this subgroup are used for atrial and ventricular arrythmia
Quinidine

Quinidine

• Subgroup IA Na+ channel blocker

• Quinidine is a D-isomer of quinine (antimalarial drug) made from it by
epimerization. It is also obtained from bark of various species of cinchona
• Class I antiarrhythmic agent that interferes with the depolarization of the cardiac
membrane,with a depressant action on the heart
• Quinidine has a direct myocardial depressant action.
– Prolong Depolarisation - Decreased conductivity
– Prolong duration of action
– Prolong effective refractory period - Decreased excitability
 SAR - Stereochemistry

• Four stereochemical centers exist in the molecule (at C-3, C-4, C-8, and C-9).
Quinine Quindine
(Antimalarial) (Antiarrhyth
mic)

Stereomers 3R, 4S,8S, 9R 3R, 4S, 8R, 9S ACTIVE

3
3
4
4
8 4
8 3
9 9
8
9

3R, 4S, 8R, 9S

Quindine
(Antiarrhythmic)
 Therapeutics

• Quinidine and its salts are used to

– prevention and treatment of atrial and ventricular
arrhythmias., and for the
– maintain sinus rhythm after cardioversion of atrial
fibrillation

• However, it is a toxic drug and is used relatively rarely.

Procainamide

• Amide analog of the local anesthetic agent procaine (which is an ester)

• As an antiarrhythmic, procainamide is preferred over procaine because
unlike procaine,
– it is better absorbed when taken orally and
– it is more difficult for the esterases of the plasma to hydrolyze it,
which results in long-lasting action.
• It is particularly effective in promptly abolishing ventricular premature
depolarization and is given for the treatment of ventricular arrhythmias
particularly those following myocardial infarction.
• It is also used for prevention of atrial and ventricular arrhythmias.
Metabolism
 Disopyramide
• Disopyramide Phosphate is approved for oral administration
in the treatment of ventricular arrhythmias as an alternative
to quinidine and procainamide.
• Disopyramide is administered as a racemic mixture, but its
antiarrhythmic activity resides primarily in the S-enantiomer.
• Disopyramide is mainly used for the prevention and treatment
of atrial and ventricular arrhythmias.
 Disopyramide
• Approximately half of an oral dose is excreted unchanged in the urine.
• The remaining drug undergoes hepatic metabolism, principally to the
corresponding N-dealkylated form.
• This metabolite retains approximately half the antiarrhythmic activity of
disopyramide and also is subject to renal excretion
• The major metabolite is mono-N-dealkylated disopyramide which retains
50% antiarrhythmic and antimuscarinic activity.
• The conversion of diisopyramide to an active metabolite results in
prolonged activity

50% active
SAR

(1) Replacement of pyridyl group with acylic amines gave good

compounds. Cyclohexyl group gave equally potent compound.
(2) 2-Pyridyl is more potent than other pyridyl isomers.
(3) Variation in the amino group resulted in only di-
isopropylamine and 2, 6-dimethylpiperidine as the most
suitable groups.
Anti-arrhythmic agents
Quinidine, Procainamide, Disopyramide*,
Lidocaine, Tocainide, Mexilitine, Phenytoin
Lorcainide,
Sotalol
Amiodarone,
Verapamil, Diltiazem
 Classification
Antiarrhythmic drugs can therefore be subdivided into four main groups.

• Na channel blockers – Class I • β-adrenergic blockers – Class II

– Class IA – Action potential duration – Sotalol
prolonged (moderate Na+ channel
blockade)
• Quinidine, Procainamide, • K channel blockers – Class III
Disopyramide
– Amiodarone
– Class IB – Action potential duration
shortened (weak Na+ channel
blockade) • Ca channels blockers – Class IV
• Lidocaine, Tocainide – Verapamil, diltiazem,
Mexiletine, Phenytoin
– Class IC – Action potential duration
unaffected (strong Na+ channel
blockade)
• Lorcainide
 Class I: Na+ Channel Blockers

• Na+ Channel Blockers affect Phase 0 of Action potential.

• This class is further subclassified into class IA, IB, and IC based on the
primary pharmacologic effect.
• IA:
• Moderate Na+ channel blockade
• Prolong APD
• IB:
• Weak Na+ channel blockade
• Shorten APD in some heart tissues
• IC:
• Strong Na+ channel blockade
• Minimal effect on APD
Classification Mechanism Primary site of Examples
action
Class IB • Have high affinity and Ventricular tissue Lidocaine
(Na+ channel stabilise the Na channels Mexiletine
blockers) which are in inactive/closed Tocainide
• Weak Na+ state
channel • suppress automatism
blockade • Once fired, they reduce the
• Shorten effective refractory period
APD in (reduce force of contraction)
some by other mechanisms
heart
tissues

Lidocaine Tocainide Mexiletine Phenytoin

Drugs of this subgroup are used for severe ventricular arrhythmia (larger no. of inactive Na
channels) that can originate during myocardial infarction, surgical intervention, catheterization of
the heart, and intoxication by cardiac glycosides.
Procainamide Lidocaine
Lidocaine
• Local anesthetic agent like procaine with distinctly different
cardiac effects
• Lidocaine is normally reserved for the treatment of ventricular
arrhythmias and is, in fact, usually the drug of choice for
emergency treatment of ventricular arrhythmias.
• Parenteral administration
– Lidocaine is effective as an antiarrhythmic only when given
parenterally
– Antiarrhythmic activity is not observed after oral
administration because of the rapid and efficient first-pass
metabolism by the liver.
 Lidocaine
• Hepatic metabolism is rapid (plasma half-life, ~15–30 minutes) and primarily
involves N-deethylation to yield monoethylglycinexylide, followed by amidase-
catalyzed hydrolysis into N-ethylglycine and 2,6-dimethylaniline (2,6-xylidine)
• Monoethylglycinexylide has good antiarrhythmic activity. It is not clinically useful,
however , because it undergoes rapid enzymatic hydrolysis.

Monoethylglycinexylide
Active, short-lived

N-ethylglycine
2,6-dimethylaniline
Tocainide
• Tocainide is an α-methyl analogue structurally related to
monoethylglycinexylide (without the ethyl), the active metabolite of
lidocaine, which possesses very similar electrophysiologic effects to
lidocaine.
• In contrast to lidocaine, tocainide is orally active, and its oral absorption is
excellent.
• Like lidocaine, it usually is reserved for the treatment of ventricular
arrhythmias.
• The α-methyl group is believed to slow the rate of metabolism and, thereby,
to contribute to oral activity.
• The plasma half-life of tocainide is approximately 12 hours, and nearly 50%
of the drug may be excreted unchanged in the urine.
• A low incidence of bone marrow depression has caused this drug to be used
less frequently than mexiletine.
 Mexiletine
• Most useful in suppressing symptomatic ventricular
arrhythmias.
• It is very similar to lidocaine in its action, but without the
amide group and with a dealkylated primary amine
• It differs from lidocaine in its suitability for oral
administration, high systemic availability (90%) after
ingestion and is metabolized by hepatic route.
• A relatively long plasma half- life of approximately 12 to 16
hours is common.
 Procainamide

Lidocaine Tocainide Mexiletine

 Phenytoin

• Phenytoin is a hydantoin derivative of the anticonvulsants class. It is useful

for the prevention of tonic-clonic seizures and focal seizures, but not
absence seizures. The intravenous form, fosphenytoin, is used for status
epilepticus that does not improve with benzodiazepines
• It is structurally dissimilar to other class I antiarrhythmic compounds and
is the only non-basic member of this family of compounds.
• However, its effects on cardiac cells are similar to those of lidocaine.
Mechanistically, it depresses ventricular automaticity and shortens the
effective refractory period relative to the action potential duration.
• It decreases the force of contraction, depresses pacemaker action, and
improves atrioventricular conduction, especially when administered in
conjunction with digitalis
Classification Mechanism Primary site of Examples
action
Class IC • Markedly depress
(Na+ channel depolarization Ventricular tissue Lorcainide
blockers) Marked decrease in
• Strong conductivity
Na+ • Minimal effect on the action
channel potential duration.
blockade
• Minimal
effect on
APD

Lorcainide

These are used for preventing and regulating ventricular arrhythmias.

Lorcainide
• Lorcainide is another benzamide-piperidine derivative
• Lorcainide is Class 1c antiarrhythmic agent
• It is used to help restore normal heart rhythm and conduction
in patients with premature ventricular contractions and
ventricular tachycardias
• It is also used in treatment of Wolff-Parkinson-White
syndrome
– pre-excitation syndrome in which individuals are
predisposed to supraventricular tachyarrhythmias (rapid
and irregular heart beats).People with this condition have
an extra or accessory atrioventricular conduction pathway
that causes re-entry tachycardia.
Mechanism
• Fast-acting voltage-gated sodium channels (Nav1.5) found in high
concentrations in the ventricular myocytes, open at a membrane potential
of −80 mv in typical cardiac rhythm.
• This will result in a rapid upstroke of an action potential that leads to
contraction of the ventricles
• Class 1c drugs have local anesthetic properties and have a high affinity for
open Nav1.5 (but not closed or inactive Nav1.5), thus irreversibly binding
and reducing the fast Na+ influx.
• Lorcainide slows conduction in myocardial tissue and reduces the speed of
depolarization of myocardial fibers, suppressing impulse conduction in the
heart
• Class 1c drugs have a characteristically slow dissociation rate, which will
slow the upstroke duration and amplitude of ventricular myocytes’ action
potential and prolong the PR, QRS and QT intervals of an ECG.
• Lorcainide also increases the ventricular fibrillation threshold in a dose-
dependent fashion
Metabolism
Norlorcainide

• The drug is administered orally and intravenously; after oral

administration, the drug is rapidly and almost completely
absorbed from the gastrointestinal tract.
• It has a half-life of almost 10 hrs which may be prolonged to
66 hrs in people with cardiac disease
• Metabolism of Lorcainide results in N-dealkylation of the
piperidyl nitrogen to yield norlorcainide.
• This metabolite is as potent as its parent compound, but its
half-life is approximately three times longer.
 Adverse reactions
• Lorcainide exhibits a prolonged duration of action
(approximately 8-10 hrs), is well absorbed when taken orally
and has a good safety profile as well as a good drug efficacy
• However, an increased prevalence of central nervous system
effects, including headache, dizziness and sleep disturbances
have been associated with oral dosages of Lorcainide when
compared to intravenous administration.
• This could be due to a greater accumulation of plasma
Norlorcainide when exposed to oral Lorcainide. Norlorcainide,
an N-dealkylated derivative, is an active metabolite of
Lorcainide. It is as potent as its parent compound with similar
antiarrhythmic efficacy, wherein it suppresses chronic
premature ventricular complexes. It has a half life of 26.5 hrs.
 pH dependent effect of Class I
Antiarrhythmics
• Sodium channel-blocking agents that are weak bases have pH-dependent
electrophysiologic effects.
• Example –
– Lidocaine is a weak base (pKa 7.913), present in both cationic and
neutral form at physiologic pH. Small changes in pH can result in
substantial changes in the ratio of charged to uncharged drug and can
account for differences in drug effects.
• In the presence of acidosis, the ratio of the effects of lidocaine are
believed to be enhanced because of higher charged-to-neutral
drug ratio, higher affinity for the Na channel and slower recovery
from lidocaine block.
• On the other hand, alkalosis causes a lower charged-to-neutral
drug ratio, decreased affinity to Na channel which results in faster
recovery from lidocaine block
Classification Mechanism Primary site of Examples
action
Class II • act at SA node and AV node SA node
(β-adrenergic • blocks sympathetic stimulation AV node
blockers) of Ca+ influx via βI adrenergic Sotalol
receptors
• Decrease the frequency of SA
node firing
• Heart rate decreases

Sotalol
Aryloxy propanol amines Aryl ethanol amines

Propanolol Sotalol
 Class II-Antiarrhythmic Drugs
β-Receptor antagonists
• These drugs are primarily effective in treatment of tachyarrhythmias
caused by increased sympathetic activity.
• Blocking sympathetic activity with -blockers
– Their dominant electrophysiological effect is on SA node and AV node
– They depress adrenergically enhanced calcium influx via β-receptor
blockade.
– They raise the threshold of excitation
– Decrease the frequency of SA node firing
– Heart rate decreases
– Used for atrial and ventricular arrhythmias
• Propranolol is the prototype β-adrenergic blocker drug for class II.
• They are used for arrhythmias associated with nervous stress, myocardial
infarction, and thyrotoxicosis accompanied by elevated adrenergic activity.
Sotalol
• (―)-Sotalol, a nonselective β-adrenergic blocker, is a methane
sulfonanilide antiarrhythmic agent.
• Sotalol is used orally to suppress and prevent the recurrence of life-
threatening ventricular arrhythmia.
• It is effective against both atrial and ventricular arrhythmias.
• It is a much safer drug than amiodarone.
• It has a long half-life (about 15 hours).
Classification Mechanism Primary site of Examples
action
Class III • K+ channel blockade Atrial and ventricular Amiodarone
(K+ channel • prolong phase 3 repolarization tissue
blockers) • prolongs duration of action
potential which
• prolongs refractory period
Decreased excitability

Amiodarone

• They are used for treating ventricular arrhythmias, which do not respond to other
antiarrhythmic drugs in life-threatening cases.
 Amiodarone Hydrochloride
• Iodinated benzofuran derivative - It has two iodide atoms and
a diethylaminoethanol group as substituents in the benzoyl
part.

• Amiodarone is highly lipid-soluble and its half-life is 20-100

days.
 Amiodarone Hydrochloride
• Amiodarone suppresses premature ventricular contractions
and ventricular tachycardia.
• Its use is reserved for the treatment of life threatening
ventricular arrhythmias refractory to other treatment.
SAR
• Iodine can be replaced by bromine and methyl without losing
activity
• Replacement of Benzofuran ring by the
– benzothiophene ring gives retention of activity.
S

– indolizine gives butoprozine with higher antiarrhythmic

activity.
 Amiodarone Hydrochloride
• Amiodarone’s antiarrhythmic action is connected to its ability to
– Not only block K, but also Na and Ca channels
– while noncompetitively blocking α- and β-adrenergic receptors of the
heart
• Thus although it is primarily a Class III agent it also mimics the actions of
Class I, II, and IV antiarrythmic.
• In addition, it’s mechanism of action also involves alteration of the lipid
membrane in which ion channels and receptors are located.
• This prolongs the action potential and effective refractive period of atrial
cells, atrioventricular junctions, and ventricles of the heart, which is
accompanied by decreased automatism of sinus node and slowing of
atrioventricular conductivity.
 Therapeutic use
• Clinical use of amiodarone is limited because of its high
toxicity, which consists of cardiac block, bradycardia, cardiac
insufficiency, damaged thyroid gland function,
neuropathology, and increased sensitivity to light, all of which
significantly limit use of amiodarone
• It is only used in therapy for extremely serious
tachyarrhythmias such as reoccurring ventricular fibrillation
and hemodynamic unstable ventricular tachycardia, and only
under supervision of a physician in a clinical situation.
Classification Mechanism Primary site of Examples
action
Class IV AV node SA node
(Ca+ channel • Ca+2 channel blockade AV node Cardiac myocyte
blockers) • Prolonging repolarization of AV
node
Decreased conductivity
Cardiac myocyte
• Short plateau
• Decreased muscle contraction
Verapamil
Diltiazem

Verapamil
Diltiazem
 Class IV Antiarrhythmic Drugs: Calcium-
channel Blockers
• Administration of a Class IV drug causes
– prolongation of the refractory
period in the AV node and the atria,
SA / AV- node
– a decrease in atrioventricular • Increased threshold
conduction, and a • (decreased excitability)
• Decreased rate of
– decrease in spontaneous diastolic depolarisation
depolarization. (decreased conductivity)
– relaxation of smooth muscle of
– heart musculature and restores
normal sinus rhythm during
CardIac myocyte
supraventricular tachycardias. • Short plateau
• These effects block conduction of • Decreased muscle
premature impulses at the AV node and contraction

thus are very effective in treating atrial

arrhythmias.
 Class IV Antiarrhythmic Drugs: Calcium-
channel Blockers
• Class IV calcium channel antiarrhythmic drugs comprise a group of agents
that selectively block the slow inward current carried by calcium ( i.e.
calcium channel blockers).
• The slow inward current in cardiac cells has been shown to be of
importance for the normal action potential in SA node cells.
• It also has been suggested that this inward current is involved in the
genesis of certain types of cardiac arrhythmias.
• Administration of a Class IV drug causes a prolongation of the refractory
period in the AV node and the atria, a decrease in AV conduction, and a
decrease in spontaneous diastolic depolarization.
• These effects block conduction of premature impulses at the AV node and,
thus, are very effective in treating supraventricular arrhythmias.
• Verapamil and diltazem are prototype drugs for this class. but
dihydropyridine drugs are less effective in cardiac tissues.
Verapamil
RS)-2-(3,4-Dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl]-
(methyl)amino}-2-prop-2-ylpentanenitrile

• The diphenylalkylamine verapamil slows cardiac

atrioventricular (AV) conduction directly, and decreases heart
rate, contractility, blood pressure, and oxygen demand.
• Verapamil causes greater negative inotropic effects than
nifedipine, but it is a weaker vasodilator.
• Verapamil is contraindicated in patients with preexisting
depressed cardiac function or AV conduction abnormalities.
• Data show a greater affinity of verapamil and other Ca2+
channel blockers to the inactivated state of the channel.
SAR
• The tertiary nitrogen atom and the chain length at the left and the right
side of this basic nitrogen are critical for biological activity.
• The length of the aliphatic side chain can be varied within a broad range.
• Tertiary nitrogen which is completely charged at physiological pH is
essential for activity.
• Benzene rings are essential for activity
• Position and nature of the aromatic substituents are not critical,
although three to five methoxy groups constitute an optimum.
• Groups longer than isopropyl group on the terminal C are found to
influence the pharmacokinetic behaviour and give a more pronounced
cardioprotective effect.
• The nitrile group is essential for activity.
SAR
 Metabolism
• It is absorbed rapidly after oral administration.
• The drug is metabolized quickly and, as a result, has low
bioavailability.
• The liver is the main site of first-pass metabolism, forming
several products.
• The preferential metabolic step involves N-dealkylation,
followed by O-demethylation, and subsequent conjugation of
the product before elimination.
• The metabolites have no significant biological activity.
• Verapamil has an elimination half-life of approximately 5
hours.
Metabolism
• Verapamil is metabolized
1. by CYP3A4 N-demethylation to its principal metabolite,
norverapamil, which retains approximately 20% of the
activity of verapamil

CH3 H
Verapamil Norverapamil
Approx 20% active
 Metabolism
• Verapamil is metabolized
2. by O-demethylation (CYP2D6) into various inactive
metabolites which are then conjugated with glucuronic
acid
Calcium channel blockers
• Benzothiazepine class of CCBs
– combine effects of the other two classes on both the heart and vascular
smooth muscle
• Diltiazem
– The drug increases myocardial oxygen supply by relieving
coronary artery spasm and reduces myocardial oxygen demand
by decreasing heart rate and reducing overload.

Benzothiazepine

Diltiazem
Diltiazem 2S

3S

[(2S, 3S)-5-[2-(dimethylamino)ethyl)]-2-(4-methoxyphenyl)-4-
oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate

• Diltiazem reduces the heart rate, although to a lesser extent

than verapamil, and also decreases blood pressure.
• In addition, diltiazem can relieve coronary artery spasm and,
therefore, is particularly useful in patients with variant angina.
• Diltiazem hydrochloride is used in patients with variant angina.
 SAR
• The most important structural feature is the
cis-arrangement of the aromatic substituent
with the acetoxy group, which is a prerequisite
for biological activity.

2S

3S
 ADME
• The drug is absorbed rapidly and almost
completely from the digestive tract.
• Diltiazem hydrochloride is metabolized
extensively after oral dosing, by first-pass
metabolism.
• As a result, the bioavailability is about 40% of
the administered dose.
 Metabolism
• The drug undergoes several biotransformations, including deacetylation, oxidative
O- and N-demethylations, and conjugation of the phenolic metabolites.
• Of the various metabolites, only the primary metabolite, deacetyldiltiazem, is
pharmacologically active.
• Deacetyldiltiazem has about 40% to 50% of the potency of the parent compound.

40 – 50% active
Classification Mechanism Primary site of Examples
action
Atrial and
Class IA • Prolong Depolarisation - Ventricular tissue
(Na+ channel Decreased conductivity Quinidine
blockers) • Prolong duration of action Procainamide
• Moderate • Prolong effective refractory Diisopyramide
Na+ channel
blockade
period - Decreased
• Prolong excitability
APD
Class IB • Have high affinity and Ventricular tissue
(Na+ channel stabilize the Na channels Lidocaine
blockers) which are in inactive/closed Tocainamide
• Weak Na+ state Mexiletine
channel
blockade • suppress automatism
• Shorten APD • Once fired, they reduce the
in some effective refractory period
heart tissues (reduce force of contraction)
Classification Mechanism Primary site of Examples
action
• Markedly depress
Class IC depolarization Ventricular tissue Propafenone
(Na+ channel Marked decrease in
blockers) conductivity
• Strong Na+ • Minimal effect on the action
channel potential duration.
blockade
• Minimal
effect on
APD
Classification Mechanism Primary site of Examples
action
Class II • blocks sympathetic stimulation SA node
(β-adrenergic of Ca+ influx via βI adrenergic AV node
blockers) receptors Propranolol
• Decrease the frequency of SA Sotalol
node firing
• Heart rate decreases

Class III • K+ channel blockade Atrial and ventricular

(K+ channel • prolong phase 3 repolarization tissue
blockers) • prolongs duration of action Amiodarone
potential which
• prolongs refractory period
Decreased excitability
Class IV SA node
(Ca+ channel AV node
blockers)
AV node Cardiac myocyte
• Ca+2 channel blockade
• Prolonging repolarization of AV
node Verapamil
Decreased conductivity Diltiazem
Cardiac myocyte
• Short plateau